Process for producing crystal

ABSTRACT

The present invention relates to a production method of a crystal of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.n′H 2 O (wherein n′ is about 0 to about 0.1) or a salt thereof, which characteristically includes crystallization from an organic solvent solution or suspension in which (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-benzimidazole.nH 2 O (wherein n is about 0.1 to about 1.0) or a salt thereof has been dissolved or suspended, and the like, and provides a convenient method for efficiently producing an optically active sulfoxide derivative having an extremely high enantiomer excess in high yield at an industrial large scale.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Division of application Ser. No. 11/515,639, filedSep. 5, 2006, which is a Division of application Ser. No. 10/275,334,filed Nov. 7, 2002, now issued U.S. Pat. No. 7,169,799, which is a U.S.National Stage of International Application No. PCT/JP01/04014, filedMay 15, 2001, which applications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a production method of an opticallyactive sulfoxide compound having an antiulcer activity.

BACKGROUND ART

As a method for producing(R)-2-[[[3-methyl-4-2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolehaving an antiulcer activity [hereinafter sometimes to be referred to asan (R)-form] or(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolehaving an antiulcer activity [hereinafter sometimes to be referred to asan (S)-form], for example, Japanese Patent Application under PCT laidopen under kohyo No. Hei 11-508590 (WO 97/02261) describes a method foroptically purifying a product prepared to be enriched in one enantiomer,which comprises adding a product prepared to contain either(+)-enantiomer or (−)-enantiomer in a greater amount than the other,namely, product prepared to be enriched in one enantiomer, to a solvent,selectively precipitating a racemic compound from the solvent utilizingthe crystallinity of racemates, filtering and removing the precipitatedracemic compound and removing the solvent to give a single enantiomerhaving an increased optical purity.

When an (R)-form or (S)-form is to be produced by asymmetric synthesis,2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole(hereinafter sometimes to be referred to as a sulfide form) is subjectedto asymmetric oxidization to give the objective (R)- or (S)-form. Inthis case, an excess reaction product,2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfonyl]benzimidazole(hereinafter sometimes to be referred to as a sulfone form), isproduced. Accordingly, the (R)-form or (S)-form obtained by asymmetricsynthesis generally includes an unreacted sulfide form as an analogoussubstance and a sulfone form as an excess reaction product.

Generally, a sulfone form present in sulfoxide having an antiulceractivity is difficult to remove. For example, JP-A-2000-16992 disclosesthat, once sulfone is produced, the yield of the objective sulfoxidedecreases, and separation and purification is problematically difficultbecause the physico-chemical properties of the both are extremelysimilar to each other. Similarly in the case of an (R)-form or (S)-form,a column chromatography treatment and the like are essential forremoving a sulfone form present as an analogous substance.

For example, in Example 21 of Japanese Patent Application under PCTlaid-open under kohyo No. Hei 10-504290 (WO 96/02535), flushchromatography was applied to obtain the object substance from asolution containing a large amount of(−)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole(11% of sulfide form and 7% of sulfone form present as analogoussubstances), after which various steps are applied to obtain the 99.5%ee objective substance in a yield of 29%. In Example 22 of thispublication, flush chromatography was applied to obtain the objectivesubstance from a solution containing a large amount of(+)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-methyl]sulfinyl]benzimidazole(13% of sulfide form and 8% of sulfone form present as analogoussubstances), after which various steps are applied to obtain the 99.6%ee objective substance in a yield of 14%.

As evidenced, conventional methods require industrially disadvantageousoperations such as chromatography and the like are necessary forremoving a sulfone form and the like, and the yield of the objectivesubstance remains at a low level.

The conventional production methods are associated with problems thatthey indispensably require purification by column chromatography and thelike to remove a sulfone form that resists separation and purification,and the objective optically active sulfoxide form shows a low enantiomerexcess (optical purity) and low yield. Therefore, a production method ofan (R)-form or (S)-form having an antiulcer activity, has been demandedwhich is industrially advantageous from the aspects of the amount ofanalogous substance present therein, enantiomer excess, yield,productivity, economic efficiency and the like.

DISCLOSURE OF THE INVENTION

The present inventors have studied the production methods of an (R)-formand an (S)-form from various aspects and have first found that an(R)-form and an (S)-form include a crystal (including solvate andhydrate) having a particular crystal form and showing physicalproperties different from those of a sulfone form; when the crystalhaving a particular crystal form is crystallized, a sulfone form thatgenerally resists removal can be unexpectedly removed easily and theobjective substance having an extremely high optical purity can beobtained; and further that this method is a production method fullysatisfactory on an industrial scale and the like, which resulted in thecompletion of the present invention.

Accordingly, the present invention relates to

-   [1] a production method for a crystal of    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-benzimidazole.n′H₂O    (wherein n′ is about 0 to about 0.1) or a salt thereof, which    comprises obtaining the crystal by crystallization from an organic    solvent solution or suspension in which    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.nH₂O    (wherein n is about 0.1 to about 1.0) or a salt thereof has been    dissolved or suspended;-   [2] the production method according to the aforementioned [1],    wherein    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.nH₂O    (wherein n is about 0.1 to about 1.0) or a salt thereof is subjected    to a dehydration step, followed by crystallization for the objective    crystal;-   [3] the production method according to the aforementioned [1],    wherein the organic solvent comprises an acetic acid C₁₋₄ alkyl    ester;-   [4] the production method according to the aforementioned [3],    wherein the acetic acid C₁₋₄ alkyl ester is ethyl acetate;-   [5] the production method according to the aforementioned [1],    wherein n is about 0.2 to about 0.8;-   [6] the production method according to the aforementioned [1],    wherein n is about 0.5;-   [7] a production method for a crystal of    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-benzimidazole.n′H₂O    (wherein n′ is about 0 to about 0.1) or a salt thereof, which is    substantially free of    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-benzimidazole    or a salt thereof, which method comprises obtaining a crystal of    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.nH₂O    (wherein n is about 0.1 to about 1.0) or a salt thereof by way of a    selective crystallization from a solution or suspension comprising    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof in a greater amount than    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof, followed by crystallization for the objective    crystal from an organic solvent solution or suspension in which the    said obtained crystal has been dissolved or suspended;-   [8] the production method according to the aforementioned [7],    wherein the selective crystallization is conducted in an organic    solvent containing water;-   [9] the production method according to the aforementioned [8],    wherein the organic solvent is one kind or more kinds selected from    esters, ketones, ethers, hydrocarbons and aromatic hydrocarbons;-   [10] the production method according to the aforementioned 1 or 7,    wherein the crystal of    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.n′H₂O    (wherein n′ is about 0 to about 0.1) shows characteristic peaks at    interplanar spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09,    3.94, 3.89, 3.69, 3.41 and 3.11 Angstroms in powder X-ray    diffraction;-   [11] a production method for a crystal of    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof, which is substantially free of    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-benzimidazole    or a salt thereof, which method comprises obtaining a crystal of    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof by a selective crystallization from a solution    comprising    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof in a greater amount than    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof and subjecting the obtained crystal to a    dehydration step, followed by crystallization for the objective    crystal;-   [12] a production method for a crystal of    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-benzimidazole.m′H₂O    (wherein m′ is about 0 to about 0.1) or a salt thereof, which    comprises obtaining the objective crystal by crystallization from an    organic solvent solution or suspension in which    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.mH₂O    (wherein m is about 0 to about 0.1) or a salt thereof has been    dissolved or suspended;-   [13] the production method according to the aforementioned 12,    wherein    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.mH₂O    (wherein m is about 0.1 to about 1.0) or a salt thereof is subjected    to a dehydration step, followed by crystallization for the objective    crystal;-   [14] the production method according to the aforementioned 12,    wherein the organic solvent comprises an acetic acid C₁₋₄ alkyl    ester;-   [15] the production method according to the aforementioned 14,    wherein the acetic acid C₁₋₄ alkyl ester is ethyl acetate;-   [16] the production method according to the aforementioned 12,    wherein m is about 0.2 to about 0.8;-   [17] the production method according to the aforementioned 12,    wherein m is about 0.5;-   [18] a production method for a crystal of    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-benzimidazole.m′H₂O    (wherein m′ is about 0 to about 0.1) or a salt thereof, which is    substantially free of    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-benzimidazole    or a salt thereof, which method comprises obtaining a crystal of    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.mH₂O    (wherein m is about 0.1 to about 1.0) or a salt thereof by a    selective crystallization from a solution or suspension comprising    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof in a greater amount than    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof, followed by crystallization for the objective    crystal from an organic solvent solution or suspension in which the    obtained crystal has been dissolved or suspended;-   [19] the production method according to the aforementioned 18,    wherein the selective crystallization is conducted in an organic    solvent containing water;-   [20] the production method according to the aforementioned 19,    wherein the organic solvent is one kind or more kinds selected from    esters, ketones, ethers, hydrocarbons and aromatic hydrocarbons;-   [21] the production method according to the aforementioned 12 or 18,    wherein the crystal of    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.m′H₂O    (wherein m′ is about 0 to about 0.1) shows characteristic peaks at    interplanar spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09,    3.94, 3.89, 3.69, 3.41 and 3.11 Angstroms in powder X-ray    diffraction;-   [22] a production method for a crystal of    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof, which is substantially free of    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-benzimidazole    or a salt thereof, which method comprises obtaining a crystal of    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof by a selective crystallization from a solution    comprising    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof in a greater amount than    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof, and subjecting the obtained crystal to a    dehydration step, followed by crystallization for the objective    crystal;-   [23] the production method according to the aforementioned 7, 11, 18    or 22, wherein    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof or    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole    or a salt thereof in the solution or suspension shows an enantiomer    excess of not less than about 80% ee;-   [24] the production method according to the aforementioned 7, 11, 18    or 22, wherein the crystal obtained by the selective crystallization    is-   (1) a crystal showing characteristic peaks at interplanar    spacings (d) of 5.88, 4.70, 4.35, 3.66 and 3.48 Angstroms in powder    X-ray diffraction;-   (2) a crystal showing characteristic peaks at interplanar    spacings (d) of 8.33, 6.63, 5.86 and 4.82 Angstroms in powder X-ray    diffraction; or-   (3) a mixture of the crystals of the above (1) and (2);-   [25] the production method according to the aforementioned 7, 11, 18    or 22, wherein the crystal obtained by the selective crystallization    is further subjected to one or more times of a crystallization step;-   [26] a crystal of    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.nH₂O    (wherein n is about 0.1 to about 1.0) or a salt thereof;-   [27] a crystal of    (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.mH₂O    (wherein m is about 0.1 to about 1.0) or a salt thereof;-   [28] the crystal according to the aforementioned 26 or 27, which    shows characteristic peaks at interplanar spacings (d) of 5.88,    4.70, 4.35, 3.66 and 3.48 Angstroms in powder X-ray diffraction;-   [29] the crystal according to the aforementioned 26 or 27, which is    a crystal shows characteristic peaks at interplanar spacings (d) of    8.33, 6.63, 5.86 and 4.82 Angstroms in powder X-ray diffraction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a powder X-ray diffraction chart of the wet crystal ofExample 3(2).

FIG. 2 shows a powder X-ray diffraction chart of the wet crystal ofExample 3(3).

FIG. 3 shows a powder X-ray diffraction chart of the wet crystal ofExample 3(4).

FIG. 4 shows a powder X-ray diffraction chart of the wet crystal ofExample 3(5).

FIG. 5 shows a powder X-ray diffraction chart of the wet crystal ofExample 4(2).

FIG. 6 shows a powder X-ray diffraction chart of the wet crystal ofExample 4(3).

FIG. 7 shows a powder X-ray diffraction chart of the wet crystal(starting material) of Example 5.

FIG. 8 shows a powder X-ray diffraction chart of the wet crystal(objective substance) of Example 5.

FIG. 9 shows a powder X-ray diffraction chart of the wet crystal ofExample 6.

FIG. 10 shows a powder X-ray diffraction chart of the wet crystal ofExample 7.

FIG. 11 shows a powder X-ray diffraction chart of the wet crystal ofExample 8.

FIG. 12 shows a powder X-ray diffraction chart of the wet crystal ofExample 9.

FIG. 13 shows a powder X-ray diffraction chart of the wet crystal ofExample 10.

FIG. 14 shows a powder X-ray diffraction chart of the wet crystal ofExample 11.

FIG. 15 shows a powder X-ray diffraction chart of the wet crystal ofExample 12.

FIG. 16 shows a powder X-ray diffraction chart of the crystal of Example13.

FIG. 17 shows a powder X-ray diffraction chart of the wet crystal ofExample 14.

FIG. 18 shows a powder X-ray diffraction chart of the crystal of Example15.

FIG. 19 shows a powder X-ray diffraction chart of the wet crystal ofExample 16.

FIG. 20 shows a powder X-ray diffraction chart of the crystal of Example17.

FIG. 21 shows a powder X-ray diffraction chart of the wet crystal ofExample 18.

FIG. 22 shows a powder X-ray diffraction chart of the crystal of Example19.

FIG. 23 shows a powder X-ray diffraction chart of the wet crystal ofExample 20.

FIG. 24 shows a powder X-ray diffraction chart of the wet crystal ofExample 21.

As the “salt” of (R)-form and the “salt” of (S)-form, pharmaceuticallyacceptable salts are preferable. For example, a salt with an inorganicbase, a salt with an organic base, a salt with a basic amino acid andthe like are mentioned.

Preferable examples of the salt with an inorganic base include alkalimetal salts (e.g., sodium salt, potassium salt etc.); alkaline earthmetal salts (e.g., calcium salt, magnesium salt etc.); ammonium salt;and the like.

Preferable examples of the salt with an organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like.

Preferable examples of the salt with an organic base include salts witharginine, lysin, ornithine and the like of these, preferred are alkalimetal salt and alkaline earth metal salt. Particularly, a sodium salt ispreferable.

An (R)-form.nH₂O (wherein n is about 0.1 to about 1.0) or a salt thereofcan be produced by selective crystallization for a crystal of an(R)-form.nH₂O (wherein n is about 0.1 to about 1.0) or a salt thereoffrom “a solution or suspension containing the (R)-form or a salt thereofin a greater amount than an (S)-form or a salt thereof”.

In addition, an (S)-form.mH₂O (wherein m is about 0.1 to about 1.0) or asalt thereof can be produced by selective crystallization for a crystalof the (S)-form.mH₂O (wherein m is about 0.1 to about 1.0) or a saltthereof from “a solution or suspension containing the (S)-form or a saltthereof in a greater amount than an (R)-form or a salt thereof”.

As used herein, “.nH₂O” and “.mH₂O” mean n-hydrate and m-hydrate,respectively.

The “solution or suspension containing the (R)-form or a salt thereof ina greater amount than an (S)-form or a salt thereof” and the “solutionor suspension containing the (S)-form or a salt thereof in a greateramount than an (R)-form or a salt thereof” can be produced by a methodknown per se, such as the method described in Japanese PatentApplication under PCT laid-open under kohyo No. Hei 10-504290 (WO96/02535) and the like or a method analogous thereto, or by thefollowing method.

2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-1H-benzimidazoleand an excess amount (about 1.5-10 equimolar amount) of an oxidizingagent (e.g., peroxides such as hydrogen peroxide,tert-butylhydroperoxide, cumene hydroperoxide etc., and the like) arereacted in the presence of a catalyst for asymmetric induction (e.g., acomplex of optically active diol, titanium(IV) alkoxide and water andthe like), an organic solvent [e.g., alcohols such as methanol, ethanol,propanol, isopropanol etc.; aromatic hydrocarbons such as benzene,toluene, xylene etc.; ethers such as diethyl ether, diisopropyl ether,butylmethyl ether, dioxane, tetrahydrofuran etc.; esters such as ethylacetate, methyl acetate etc.; ketones such as acetone, methyl isobutylketone etc.; halogenated hydrocarbons such as chloroform,dichloromethane, ethylene dichloride, carbon tetrachloride etc.; amidessuch as N,N-dimethylformamide etc.; sulfoxides such as dimethylsulfoxide etc.; acetic acid etc.] and a base [e.g., inorganic bases suchas alkali metal carbonate (e.g., potassium carbonate, sodium carbonateetc.), alkali metal hydroxides (e.g., sodium hydroxide, potassiumhydroxide etc.), alkali metal hydride (e.g., sodium hydride, potassiumhydride etc.), and the like; organic bases such as alkali metalalkoxides (e.g., sodium methoxide, sodium ethoxide etc.), alkali metalcarboxylate (e.g., sodium acetate etc.), amines (e.g., piperidine,piperazine, pyrrolidine, morpholine, triethylamine, tripropylamine,tributylamine, trioctylamine, diisopropylethylamine, dimethylphenylamineetc.), pyridines (e.g., pyridine, dimethylaminopyridine etc.), and thelike; basic amino acids (e.g., arginine, lysin, ornithine etc.); and thelike] at about −20 to 20° C. for about 0.1 to 50 hr to give the“solution or suspension containing the (R)-form or a salt thereof in agreater amount than the (S)-form or a salt thereof” and the “solution orsuspension containing an (S)-form or a salt thereof in a greater amountthan an (R)-form or a salt thereof”.

The “(R)-form or a salt thereof” and “(S)-form or a salt thereof” in theabove-mentioned solution or suspension may be either a solid (crystal,amorphous) or an oily substance, and may or may not be isolated orpurified.

As a solvent to prepare the “solution or suspension”, for example,water, esters, ketones, phenols, alcohols, ethers, aromatichydrocarbons, amides, sulfoxides, hydrocarbons, nitrites, halogenatedhydrocarbons, pyridines, a mixture of two or more thereof and the likeare used.

The enantiomer excess of the (R)-form or a salt thereof or (S)-form or asalt thereof in a solution or suspension is, for example, not less thanabout 80% ee, preferably not less than about 90% ee.

The method for “selective crystallization” includes, for example, amethod of stirring the solution or suspension, a method of adding a seedcrystal to the solution or suspension, a method of changing thetemperature of the solution or suspension, a method of changing thesolvent composition of the solution or suspension, a method of reducingthe liquid amount of the solution or suspension, or a combination of twoor more of these methods and the like.

As the “method of stirring the solution or suspension”, for example, amethod comprising stirring a solution or a suspension containing one of(R)-form or a salt thereof and an (S)-form or a salt thereof in agreater amount than the other at about −80 to 120° C., preferably about−20 to 60° C., for about 0.01 to 100 hr, preferably about 0.1 to 10 hr,is mentioned.

As the “method of adding a seed crystal to the solution or suspension”,for example, a method comprising adding, (1) a crystal showingcharacteristic peaks at interplanar spacings (d) of 5.88, 4.70, 4.35,3.66 and 3.48 Angstroms in powder X-ray diffraction, (2) a crystalshowing characteristic peaks at interplanar spacings (d) of 8.33, 6.63,5.86 and 4.82 Angstroms in powder X-ray diffraction, (3) a mixture ofthe crystals of the aforementioned (1) and (2), or (4) a solid thatconverts to the aforementioned (1) to (3) in a solution or suspension(e.g., a crystal showing characteristic peaks at interplanar spacings(d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41 and3.11 Angstroms in powder X-ray diffraction, a crystal showingcharacteristic peaks at interplanar spacings (d) of 11.68, 6.77, 5.84,5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41 and 3.11 Angstroms in powderX-ray diffraction, a crystal showing characteristic peaks at interplanarspacings (d) of 8.37, 4.07, 5.65, 5.59, 5.21, 4.81 and 4.21 Angstroms inpowder X-ray diffraction and the like), as a seed crystal, to a solutionor a suspension containing one of (R)-form or a salt thereof and an(S)-form or a salt thereof in a greater amount than the other, ismentioned.

As the “method of changing the temperature of the solution orsuspension”, for example, a method for changing the temperature of asolution or a suspension containing one of an (R)-form or a salt thereofand an (S)-form or a salt thereof in a greater amount than the other,preferably a method for cooling (e.g., lower the liquid temperature by 5to 100° C.), are mentioned.

As the “method of changing the solvent composition of the solution orsuspension”, for example, a method for adding water, an organic solvent(e.g., esters, ketones, phenols, alcohols, ethers, aromatichydrocarbons, amides, sulfoxides, hydrocarbons, nitrites, halogenatedhydrocarbons, pyridines or a mixture of two or more kinds of these;preferably a low polarity organic solvent (e.g., esters, ethers,aromatic hydrocarbons, hydrocarbons, halogenated hydrocarbons or amixture of two or more kinds thereof, and the like), ketones or amixture of two or more kinds thereof) to a solution or a suspensioncontaining one of an (R)-form or a salt thereof and an (S)-form or asalt thereof in a greater amount than the other, is mentioned.Preferably, a method for adding one or more kinds selected from theorganic solvents such as esters, ketones, ethers and hydrocarbons in thepresence of water, is mentioned.

As a method for addition, a method comprising dropwise adding, understirring, water, an organic solvent or a mixture thereof to a solutionor a suspension containing one of an (R)-form or a salt thereof and an(S)-form or a salt thereof in a greater amount than the other, a methodcomprising dropwise adding, under stirring, water, an organic solvent ora mixture thereof to a solution or a suspension containing one of an(R)-form or a salt thereof and an (S)-form or a salt thereof in agreater amount than the other and the like are mentioned.

As the “method of reducing the liquid amount of the solution orsuspension”, for example, a method comprising removing and evaporatingthe solvent from a solution or a suspension containing one of an(R)-form or a salt thereof and an (S)-form or a salt thereof in agreater amount than the other, and the like are mentioned.

of these, preferred are

-   (i) a method for stirring a solution or suspension,-   (ii) a method for changing the solvent composition of a solution or    suspension,-   (iii) a method comprising both a method for stirring a solution or    suspension and a method for adding a seed crystal to a solution or    suspension,-   (iv) a method comprising both a method for stirring a solution or    suspension and a method for changing the temperature of a solution    or suspension,-   (v) a method comprising both a method for stirring a solution or    suspension and a method for changing the solvent composition of a    solution or suspension,-   (vi) a method comprising both a method for stirring a solution or    suspension and a method for reducing the liquid amount of a solution    or suspension,-   (vii) a method comprising a method for stirring a solution or    suspension, a method for changing the temperature of a solution or    suspension and a method for adding a seed crystal to a solution or    suspension,-   (viii) a method comprising a method for stirring a solution or    suspension, a method for changing the solvent composition of a    solution or suspension and a method for adding a seed crystal to a    solution or suspension,-   (ix) a method comprising a method for stirring a solution or    suspension, a method for reducing the liquid amount of a solution or    suspension and a method for adding a seed crystal to a solution or    suspension,-   (x) a method comprising a method for stirring a solution or    suspension, a method for changing the temperature of a solution or    suspension and a method for changing the solvent composition of a    solution or suspension,-   (xi) a method comprising a method for stirring a solution or    suspension, a method for changing the temperature of a solution or    suspension, a method for changing the solvent composition of a    solution or suspension and a method for adding a seed crystal to a    solution or suspension,-   (xii) a method comprising a method for stirring a solution or    suspension, a method for changing the temperature of a solution or    suspension and a method for reducing the liquid amount of a solution    or suspension, and-   (xiii) a method comprising a method for stirring a solution or    suspension, a method for changing the temperature of a solution or    suspension, a method for reducing the liquid amount of a solution or    suspension and a method for adding a seed crystal to a solution or    suspension.

Of the above-mentioned methods, the methods of (ii), (v) and (x) arepreferable, and the method of (x) is more preferable.

More preferable embodiment of the method of “selective crystallization”is shown in the following.

In a solution or a suspension containing one of an (R)-form or a saltthereof and an (S)-form or a salt thereof in a greater amount than theother, the organic solvent contained in the solution or suspension isparticularly preferably a mixture of 1 or 2 or 3 kinds selected fromesters, ketones, ethers, hydrocarbons and aromatic hydrocarbons, morepreferably C₆₋₁₀ alkane (e.g., hexane, heptane, octane etc.), t-butylmethyl ether, diethyl ether, diisopropyl ether, acetone, toluene,xylene, a mixture thereof and the like.

The organic solvent to be added in the presence of water is particularlypreferably a mixture of hydrocarbons (e.g., C₆₋₁₀ alkane such as hexane,heptane, octane etc., and the like) and ethers (e.g., t-butyl methylether, diethyl ether, diisopropyl ether etc.), ketones (e.g., acetoneetc.) and the like.

As a method for addition, a mixture of water and an organic solvent isadded dropwise under stirring to a solution or suspension containing oneof an (R)-form or a salt thereof and an (S)-form or a salt thereof in agreater amount than the other, or a solution or suspension containingone of an (R)-form or a salt thereof and an (S)-form or a salt thereofin a greater amount than the other is added dropwise under stirring to amixture of water and an organic solvent, and the like. When desired,water may be further added dropwise.

Therefore, selective crystallization is preferably conducted in anorganic solvent containing water.

By the method of selective crystallization, when, for example, an(R)-form or a salt thereof or (S)-form or a salt thereof obtained byasymmetric synthesis is used, the amount of an analogous substance(e.g.,2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazoleand (or)2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]-sulfonyl]benzimidazoleand the like) in the precipitated crystals can be reduced.

The crystal obtained by crystallization can be separated and collectedby the method of, for example, filtration, centrifugation and the like.

Examples of the crystal obtained by selective crystallization accordingto the above-mentioned method include an (R)-form.nH₂O (wherein n isabout 0.1 to about 1.0), a salt thereof, an (S)-form.mH₂O (wherein m isabout 0.1 to about 1.0), a salt thereof and the like.

The “n” or “m” is preferably about 0.2 to about 0.8, particularlypreferable about 0.5.

By crystallization from an organic solvent solution or suspensionwherein the thus-obtained crystal [e.g., crystal of the above-mentioned(R)-form.nH₂O (wherein n is about 0.1 to about 1.0) or a salt thereof oran (S)-form.mH₂O (wherein m is about 0.1 to about 1.0) or a saltthereof] has been dissolved or suspended, a crystal of an (R)-form.n′H₂O(wherein n′ is about 0 to about 0.1) or a salt thereof or an(S)-form.m′H₂O (wherein m′ is about 0 to about 0.1) or a salt thereofcan be produced.

Here, the relationship between n and n′, and m and m′ in theabove-mentioned steps is n>n′ and m>m′. Therefore, for example, when nor m is 0.1, the corresponding n′ and m′ is less than 0.1.

The organic solvent to be used for dissolving or suspending includes,for example, esters, ketones, phenols, alcohols, ethers, aromatichydrocarbons, amides, sulfoxides, hydrocarbons, nitrites, halogenatedhydrocarbons, pyridines, a mixture of two or more thereof, and the like,preferably esters, hydrocarbons and a mixture thereof. Of these, anorganic solvent containing esters such as acetic acid C₁₋₄ alkyl ester(e.g., ethyl acetate, propyl acetate, butyl acetate etc.) and the likeare preferable.

More preferred are acetic acid C₁₋₄ alkyl ester (e.g., ethyl acetate,propyl acetate, butyl acetate etc.), C₆₋₈ hydrocarbons (e.g., C₆₋₈alkane such as hexane, heptane, octane etc., and the like) and a mixturethereof and the like.

For crystallization, for example, a crystal of the above-mentioned(R)-form.nH₂O (wherein n is about 0.1 to about 1.0) or a salt thereof oran (S)-form.mH₂O (wherein m is about 0.1 to about 1.0) or a salt thereofis preferably dissolved or suspended in an organic solvent, subjected toa dehydration step and then subjected to crystallization. In theproduction method of the present invention, the step for“crystallization from an organic solvent solution or suspension” mayinclude the “dehydration step” and the “crystallization step”.

The dehydration step may include a general dehydration method, such as amethod comprising dissolving or suspending the above-mentioned crystalof (R)-form.nH₂O (wherein n is about 0.1 to about 1.0) or a salt thereofor (S)-form.mH₂O (wherein m is about 0.1 to about 1.0) or a salt thereofin an organic solvent such as esters, ketones, phenols, alcohols,ethers, aromatic hydrocarbons, amides, sulfoxides, hydrocarbons,nitrites, halogenated hydrocarbons, pyridines, a mixture of two or morekinds thereof and the like, preferably esters such as acetic acid C₁₋₄alkyl ester (e.g., ethyl acetate, propyl acetate, butyl acetate etc.)and the like, which is followed by a method of partitioning, a method ofconcentration, a method using a dehydrating agent [e.g., anhydrousmagnesium sulfate, anhydrous sodium sulfate, molecular sieve (productname)], or a combination of these methods and the like.

The above-mentioned method of concentration is preferably carried outunder reduced pressure.

After the dehydration step, the objective crystal can be obtained bycrystallization (recrystallization) from a solution or suspension of theobtained crystal in an organic solvent [e.g., esters, ketones, phenols,alcohols, ethers, aromatic hydrocarbons, amides, sulfoxides,hydrocarbons, nitrites, halogenated hydrocarbons, pyridines, a mixtureof two or more kinds thereof and the like, preferably hydrocarbons suchas C₆₋₈ hydrocarbons (e.g., C₆₋₈ alkane such as hexane, heptane, octaneetc., and the like) and the like].

In the following, a step for crystallization from an organic solventsolution or suspension, wherein a crystal of an (R)-form.nH₂O (wherein nis about 0.1 to about 1.0) or a salt thereof or an (S)-form.mH₂O(wherein m is about 0.1 to about 1.0) or a salt thereof has beendissolved or suspended, is described in detail.

First, a crystal of an (R)-form.nH₂O (wherein n is about 0.1 to about1.0) or a salt thereof or an (S)-form.mH₂O (wherein m is about 0.1 toabout 1.0) or a salt thereof obtained by the above-mentioned method, asit is or after drying as necessary, is subjected to a crystallizationstep (once or more, preferably two or three times) (the crystallizationstep may include a step of dissolving or suspending in a solvent, arecrystallization step, a dehydration step and the like) as necessary.In one or more times of the crystallization step, a dehydration step ispreferably included immediately before the final crystallization(recrystallization) step.

For the “drying”, for example, vacuum drying, through-flow drying,drying by heating, air drying and the like are mentioned.

Specifically, the obtained crystal or a dried crystal thereof isdissolved or suspended in a solvent (e.g., water, esters, ketones,phenols, alcohols, ethers, aromatic hydrocarbons, amides, sulfoxides,hydrocarbons, nitrites, halogenated hydrocarbons, pyridines or a mixtureof two or more kinds thereof and the like, preferably a mixture of waterand one or more (preferably two or three) kinds of organic solvent(s)selected from hydrocarbons [e.g., C₆₋₈ hydrocarbons (e.g., C₆₋₈ alkanesuch as hexane, heptane, octane etc., and the like) and the like],aromatic hydrocarbons (e.g., toluene, xylene etc.), ketones (e.g.,acetone etc.) and ethers (e.g., t-butyl methyl ether, diethyl ether,diisopropyl ether), and after subjecting to a dehydration step asnecessary, a crystal is obtained by crystallization.

Preferably, the obtained crystal or a dried crystal thereof is subjectedto the above-mentioned crystallization step (once or more, preferablytwo or three times), subjected to a dehydration step immediately beforethe final crystallization step (recrystallization), and the objectivecrystal is obtained by crystallization.

For the “dehydration”, methods similar to the above-mentioneddehydration methods are exemplified.

For the “crystallization” method in the above-mentioned once or more,preferably two or three times of crystallization, the method describedin the aforementioned “method for selective crystallization” ismentioned. The method for crystallization to obtain the objectivecrystal after subjecting to the dehydration step preferably comprisesrecrystallization from a solution or suspension of the crystal obtainedby dehydration step in an organic solvent [e.g., esters, ketones,phenols, alcohols, ethers, aromatic hydrocarbons, amides, sulfoxides,hydrocarbons, nitrites, halogenated hydrocarbons, pyridines, a mixtureof two or more kinds thereof and the like, preferably hydrocarbons suchas C₆₋₈ hydrocarbons (e.g., C₆₋₈ alkane such as hexane, heptane, octaneetc., and the like), and the like].

As the crystal obtained by the above-mentioned crystallization step(recrystallization), there may be included

-   (1) a crystal showing characteristic peaks at interplanar    spacings (d) of 5.88, 4.70, 4.35, 3.66 and 3.48 Angstroms in powder    X-ray diffraction of undried crystal,-   (2) a crystal showing characteristic peaks at interplanar    spacings (d) of 8.33, 6.63, 5.86 and 4.82 Angstroms in powder X-ray    diffraction of undried crystal,-   (3) a mixture of the crystals of the aforementioned (1) and (2) or-   (4) a crystal showing characteristic peaks at interplanar    spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89,    3.69, 3.41 and 3.11 Angstroms in powder X-ray diffraction and the    like.

The amount of analogous substances in the crystal is less than 1 wt %,preferably less than 0.4 wt %.

The crystal obtained by the above-mentioned crystallization step (e.g.,recrystallization etc.) can be separated and collected by a method suchas filtration, centrifugation and the like.

The crystal (objective crystal) obtained by the above-mentioned finalcrystallization step (recrystallization) may be a crystal of an (R)- oran (S)-form showing characteristic peaks at interplanar spacings (d) of11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41 and 3.11Angstroms in powder X-ray diffraction and the like.

The separated and collected crystal can be dried by a method such asvacuum drying, through-flow drying, drying by heating, air drying andthe like.

The “Crystal of an (R)-form.n′H₂O (wherein n′ is about 0 to about 0.1)or a salt thereof” or “a crystal of an (R)-form or a salt thereof, whichis substantially free of an (S)-form or a salt thereof”, which isfinally crystallized out in the present invention, means a crystal of an(R)-form or a salt thereof which contains an (S)-form or a salt thereofin a proportion of 0 to 3%, preferably 0 to 1%.

The “crystal of an (S)-form.m′H₂O (wherein m′ is about 0 to about 0.1)or a salt thereof” or “a crystal of an (S)-form or a salt thereof, whichis substantially free of an (R)-form or a salt thereof”, which iscrystallized out in the present invention means a crystal of an (S)-formor a salt thereof which contains an (R)-form or a salt thereof in aproportion of 0-1%.

As used herein, the above-mentioned “.n′H₂O” and “.m′H₂O” meann′-hydrate and m′-hydrate, respectively.

In the production method of the present invention, a crystal almost freeof hydrate water or an anhydrous crystal, such as an (R)-form.n′H₂O(wherein n′ is about 0 to about 0.1) or a salt thereof or an(S)-form.m′H₂O (wherein m′ is about 0 to about 0.1) or a salt thereof,can be obtained by, for example, the above-mentioned one or more times,preferably two or three times, of the crystallization step, then adehydration step and the final crystallization step. Such crystal isexemplified by a crystal showing characteristic peaks at interplanarspacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69,3.41 and 3.11 Angstroms in powder X-ray diffraction.

The “n′” and “m′” are preferably about 0 to about 0.1. Particularly, nis 0 and m is 0, or an anhydrous crystal, is more preferable.

As the aforementioned “esters”, for example, acetic acid C₁₋₄ alkylester such as methyl acetate, ethyl acetate, propyl acetate, isopropylacetate, butyl acetate, isobutyl acetate and the like, ethyl formate andthe like can be mentioned.

As the aforementioned “ketones”, for example, acetone, methyl ethylketone, methyl isopropyl ketone, methyl butyl ketone, methyl isobutylketone and the like can be mentioned.

As the aforementioned “phenols”, for example, anisole and the like canbe mentioned.

As the aforementioned “alcohols”, for example, lower alcohols such asmethanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,2-methyl-1-propanol, pentanol, 3-methyl-1-butanol and the like; loweralcohols substituted by C₁₋₃ alkoxy such as 2-methoxyethanol,2-ethoxyethanol and the like; ethylene glycol and the like can bementioned.

As the aforementioned “ethers”, for example, t-butyl methyl ether,diethyl ether, 1,1-diethoxypropane, 1,1-dimethoxypropane,2,2-dimethoxypropane, isopropyl ether, tetrahydrofuran,methyltetrahydrofuran and the like can be mentioned.

As the aforementioned “aromatic hydrocarbons”, for example,chlorobenzene, toluene, xylene, cumene and the like can be mentioned.

As the aforementioned “amides”, for example, formamide,N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone andthe like can be mentioned.

As the aforementioned “sulfoxides”, for example, dimethyl sulfoxide andthe like can be mentioned.

As the aforementioned “hydrocarbons”, for example, C₃₋₁₀ alkane such aspropane, butane, pentane, hexane, heptane, octane, isooctane and thelike, preferably C₆₋₁₀ alkane, can be mentioned.

As the aforementioned “nitriles”, for example, acetonitrile and the likecan be mentioned.

As the aforementioned “halogenated hydrocarbons”, for example, C₁₋₆alkane optionally substituted by 1 to 5 halogens (e.g., fluorine,chlorine, bromine, iodine), such as chloroform, dichloromethane,dichloroethene, trichloroethene and the like, can be mentioned.

As the aforementioned “pyridines”, for example, pyridine and the likecan be mentioned.

The crystal obtained by crystallization by the method of the presentinvention or a dried crystal thereof is useful as a pharmaceuticalproduct because it does not substantially contain an enantiomer, has asuperior antiulcer activity, a gastric acid secretion-inhibitory action,a mucosa-protecting action, an anti-Helicobacter pylori action and thelike and shows low toxicity. A dried crystal of an (R)-form or an(S)-form or a salt thereof is stabler than a crystal as justcrystallized (undried crystal) of an (R)-form or an (S)-form or a saltthereof. Therefore, for use as a pharmaceutical product, a crystal as adried product of an (R)-form or an (S)-form or a salt thereof ispreferably used. For example, a crystal or a dried crystal obtained bycrystallization by the method of the present invention is useful for theprophylaxis or treatment of digestive ulcer (e.g., gastric ulcer,duodenal ulcer, stomach ulcer, Zollinger-Ellison syndrome, etc.),gastritis, reflux esophagitis, NUD (Non-Ulcer Dyspepsia), gastric cancer(inclusive of gastric cancer caused by promotion of interleukin-1βproduction due to genetic polymorphism of interleukin-1) and gastricMALT lymphoma; eradication of Helicobacter pylori; suppression of uppergastrointestinal hemorrhage due to digestive ulcer, acute stress ulcerand hemorrhagic gastritis; suppression of upper gastrointestinalhemorrhage due to invasive stress (stress from major surgerynecessitating intensive management after surgery, and from cerebralvascular disorder, head trauma, multiple organ failure and extensiveburn necessitating intensive treatment); treatment and prevention ofulcer caused by a nonsteroidal anti-inflammatory agent; treatment andprevention of hyperacidity and ulcer due to postoperative stress;pre-anesthetic administration and the like, in mammals (e.g., human,simian, sheep, bovine, horse, dog, cat, rabbit, rat, mouse and thelike). For eradication of Helicobacter pylori, the crystal or drycrystal obtained by the method of the present invention and antibioticpenicillins (e.g., amoxicillin etc.) and antibiotic erythromycins (e.g.,clarithromycin, etc.) are preferably used.

EXAMPLES

The present invention is described in more detail in the following bymeans of Reference Examples and Examples, which are not to be construedas limitative.

The powder X-ray diffraction was measured using an X-ray DiffractometerRINT Ultima+ (Rigaku).

The enantiomer excess (% ee) was measured by high performance liquidchromatography using the optically active column under the followingcondition (A).

The amount of the sulfide form and sulfone form present therein wasmeasured by high performance liquid chromatography using the opticallyactive column under the following condition (A) or high performanceliquid chromatography under condition (B).

-   high performance liquid chromatography condition (A);-   column: CHIRALCEL OD (manufactured by Daicel Chemical Industries,    Ltd.)-   mobile phase: hexane/ethanol=90/10-   flow rate: 1.0 ml/min-   detection: UV 285 nm-   high performance liquid chromatography condition (B);-   column: Capcell Pak (manufactured by Shiseido Company, Ltd.) mobile    phase: acetonitrile:water:triethylamine mixed solution (50:50:1)    adjusted to pH 7.0 by addition of phosphoric acid.-   flow rate: 1.0 ml/min-   detection: UV 285 nm

Reference Example 1 Production of Solution Containing (R)-Form or(S)-Form by Asymmetric Oxidization

Under a nitrogen atmosphere,2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole(50.0 g, 0.14 mol, containing 16.7 mg of water), toluene (250 ml), water(283 mg, 0.016 mol, total amount of water 0.017 mol), diethyl(+)-tartrate (10.6 ml, 0.062 mol) were mixed, and the mixture wasstirred at 50 to 55° C. for 30 min. Under a nitrogen atmosphere,titanium(IV) isopropoxide (8.29 ml, 0.028 mol) was added and the mixturewas stirred at 50 to 55° C. for 1 hr. Under nitrogen atmosphere andunder cooling, diisopropylethylamine (8.13 ml, 0.047 mol) was added tothe obtained mixture and cumene hydroperoxide (76.50 ml, content 82%,0.43 mol) was added at −10 to 0° C. The mixture was stirred at −10 to10° C. for 4.5 hr to allow reaction.

As a result of the analysis of the reaction mixture by high performanceliquid chromatography (condition (A)), 0.74% of a sulfide form and 1.46%of a sulfone form were present as analogous substances in the reactionmixture, and other analogous substances were not present. The enantiomerexcess of an (R)-form in the reaction mixture was 96.5% ee.

Example 1 Production Method of (R)-Form

To the reaction mixture obtained according to Reference Example 1[containing 14.63 g of a mixture of an (R)-form and an (S)-form,enantiomer excess 97.0% ee] was added dropwise heptane (200 ml) at 0 to10° C., and the mixture was stirred at the same temperature for 2 hr.After stirring, the precipitated crystal was collected by filtration togive a wet crystal of an (R)-form (yield (amount) after drying: 12.96 g,yield (percentage) after drying: 88.6%) having the following interplanarspacing (d) in powder X-ray diffraction.

The results of the powder X-ray diffraction analysis of this wet crystalare shown in the following.

This wet crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 5.88, 4.70, 4.35,3.66 and 3.48 Angstroms in powder X-ray diffraction.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), the enantiomer excess of the crystal was100% ee.

Example 2 Production Method of (R)-Form

Using the reaction mixture produced according to Reference Example 1,(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole(13.0 g, enantiomer excess 100% ee, containing sulfone form 1.5%)obtained according to Example 1 was dissolved in acetone (100 ml). Tothe obtained solution was dropwise added water (360 ml), and the mixturewas stirred under ice-cooling for 1 hr. The precipitated crystal wasseparated to give a wet crystal of an (R)-form (yield (amount) afterdrying: 12.5 g, yield (percentage) after drying: 96.2%) having thefollowing interplanar spacing (d) in powder X-ray diffraction.

The results of the powder X-ray diffraction analysis of this wet crystalare shown in the following.

This wet crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. The crystal was analyzed byhigh performance liquid chromatography (condition (B)), and as a result,the proportion of a sulfone form in the crystal was 0%, and otheranalogous substances were not present.

Example 3 Production Method of (R)-Form

-   (1) Under a nitrogen stream,    2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole    (4.5 kg, 12.7 mol, containing 1.89 g of water), toluene (22 L),    water (25 g, 1.39 mol, total amount of water 1.49 mol) and diethyl    (+)-tartrate (0.958 L, 5.60 mol) were mixed. Under a nitrogen    stream, titanium(IV) isopropoxide (0.747 L, 2.53 mol) was added to    the mixture at 50 to 60° C., and the mixture was stirred at the same    temperature for 30 min. Under a nitrogen stream,    diisopropylethylamine (0.733 L, 4.44 mol) was added to the obtained    mixture at room temperature, cumene hydroperoxide (6.88 L, content    82%, 37.5 mol) was added at −5 to 5° C., and the mixture was stirred    at −5 to 5° C. for 1.5 hr to give a reaction mixture.

As a result of the analysis of the reaction mixture by high performanceliquid chromatography (condition (B)), 1.87% of a sulfide form and 1.59%of a sulfone form were present as analogous substances in the reactionmixture, and other analogous substances were not present.

-   (2) To the reaction mixture obtained in the above-mentioned (1) was    added 30% aqueous sodium thiosulfate solution (17 L) under a    nitrogen stream to decompose the remaining cumene hydroperoxide. The    mixture was partitioned and to the obtained organic layer were    successively added water (4.5 L), heptane (13.5 L), t-butyl methyl    ether (18 L) and heptane (27 L). The mixture stirred at about 10° C.    to allow crystallization. The crystal was separated and washed with    t-butyl methyl ether-toluene (t-butyl methyl ether:toluene=4:1)    (4 L) to give an (R)-form having the following interplanar    spacing (d) in powder X-ray diffraction as a wet crystal.

The results of the powder X-ray diffraction analysis of this wet crystalare shown in the following.

This wet crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 5.88, 4.70, 4.35,3.66 and 3.48 Angstroms in powder X-ray diffraction. A chart of thepowder X-ray diffraction is shown in FIG. 1.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), 0.90% of a sulfone form was present asan analogous substance in the crystal, and a sulfide form and otheranalogous substances were not present. The enantiomer excess of the(R)-form in the crystal was 100% ee.

-   (3) Under stirring, a suspension of the wet crystal obtained in the    above-mentioned (2) in acetone (20 L) was added dropwise to a    mixture of acetone (7 L) and water (34 L), and then water (47 L) was    added. The mixture was stirred at about 10° C. and the precipitated    crystal was separated, and washed with acetone-water    (acetone:water=1:3) (4 L) and water (12 L) to give an (R)-form    having the following interplanar spacing (d) in powder X-ray    diffraction as a wet crystal.

The results of the powder X-ray diffraction analysis of this wet crystalare shown in the following.

This wet crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. A chart of the powder X-raydiffraction is shown in FIG. 2.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), a sulfone form, a sulfide form and otheranalogous substance were not present as analogous substances in thecrystal. The enantiomer excess of the (R)-form in the crystal was 100%ee.

-   (4) The wet crystal obtained in the above-mentioned (3) was    dissolved in ethyl acetate (45 L) and water (3 L), and then    partitioned. A trace amount of an insoluble material in the organic    layer was filtered off and triethylamine (0.2 L) was added. The    mixture was concentrated under reduced pressure to a liquid amount    of about 7 L. To the concentrate were added methanol (2.3 L), about    12.5% aqueous ammonia (23 L) at about 50° C., and t-butyl methyl    ether (22 L) at about 50° C. for partitioning. About 12.5% aqueous    ammonia (11 L) was added to the organic layer for partitioning (this    operation was repeated one more time). The aqueous layers were    combined and ethyl acetate (22 L) was added, after which acetic acid    was added dropwise under cooling to adjust its pH to about 8. The    solution was partitioned and an aqueous layer was extracted with    ethyl acetate (11 L). The organic layers were combined and washed    with about 20% brine (11 L). Triethylamine (0.2 L) was added and the    organic layer was concentrated under reduced pressure. Acetone (5 L)    was added to the concentrate and the mixture was concentrated under    reduced pressure. The concentrate was dissolved in acetone (9 L) and    the solution was added dropwise to a mixture of acetone (4.5 L) and    water (22.5 L). Then, water (18 L) was added dropwise to the    obtained mixture, and the mixture was stirred at about 10° C. The    precipitated crystal was separated and washed successively with cold    acetone-water (1:3) (3 L) and water (12 L) to give an (R)-form    having the following interplanar spacing (d) in powder X-ray    diffraction as a wet crystal.

The results of the powder X-ray diffraction analysis of this wet crystalare shown in the following.

This wet crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. A chart of the powder X-raydiffraction is shown in FIG. 3.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), a sulfone form, a sulfide form and otheranalogous substance were not present as analogous substances in thecrystal. The enantiomer excess of the (R)-form in the crystal was 100%ee.

-   (5) The wet crystal obtained in the above-mentioned (4) was    dissolved in ethyl acetate (32 L). The separated aqueous layer was    separated by partitioning and the obtained organic layer was    concentrated under reduced pressure to a liquid amount of about    14 L. To the residue were added ethyl acetate (36 L) and active    carbon (270 g), and the mixture was stirred and the active carbon    was removed by filtration. The filtrate was concentrated under    reduced pressure to the liquid amount of about 14 L. Heptane (90 L)    was added dropwise at about 40° C. to the residue. After stirring at    the same temperature for about 30 min, the crystal was separated and    washed with ethyl acetate-heptane (1:8, 6 L) at about 40° C. Drying    gave the title compound (3.4 kg).

The results of the powder X-ray diffraction analysis of this crystal areshown in the following.

The crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 11.68, 6.77, 5.84,5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41, 3.11 Angstroms in powder X-raydiffraction. A chart of the powder X-ray diffraction is shown in FIG. 4.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), a sulfone form, a sulfide form and otheranalogous substance were not present as analogous substances in thecrystal. The enantiomer excess of the (R)-form in the crystal was 100%ee.

Example 4 Production Method of (S)-Form

-   (1) Under a nitrogen atmosphere,    2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole    (50.0 g, 0.14 mol, containing 20 mg of water), toluene (250 ml),    water (130 mg, 0.0072 mol, total amount of water 0.0083 mol) and    diethyl (−)-tartrate (5.31 ml, 0.031 mol) were mixed. Under a    nitrogen atmosphere, titanium(IV) isopropoxide (4.14 ml, 0.014 mol)    was added to the mixture at 50° C., and the mixture was stirred at    50 to 55° C. for 1 hr. Under a nitrogen atmosphere and under    cooling, diisopropylethylamine (8.13 ml, 0.047 mol) was added to the    obtained mixture and cumene hydroperoxide (76.50 ml, content 82%,    0.42 mol) was added to the mixture at −10 to 0° C., and the mixture    was stirred at −5 to 5° C. for 3.5 hr to give a reaction mixture.

As a result of the analysis of the reaction mixture by high performanceliquid chromatography (condition (A)), the enantiomer excess of the(S)-form in the reaction mixture was 96.5% ee.

As a result of the analysis of the reaction mixture by high performanceliquid chromatography (condition (B)), 1.90% of a sulfone form and 1.50%of a sulfide form were present as analogous substances in the reactionmixture, and other analogous substances were not present.

-   (2) To the reaction mixture obtained in the above-mentioned (1) was    added 30% aqueous sodium thiosulfate solution (180 ml) under a    nitrogen stream to decompose the remaining cumene hydroperoxide.    After partitioning, to the obtained organic layer were added    successively water (50 ml), heptane (150 ml), t-butyl methyl ether    (200 ml) and heptane (300 ml) to allow crystallization. The crystal    was separated and washed with t-butyl methyl ether-toluene (t-butyl    methyl ether:toluene=4:1) (45 ml) to give an (S)-form having the    following interplanar spacing (d) in powder X-ray diffraction as a    wet crystal.

The results of the powder X-ray diffraction analysis of this wet crystalare shown in the following.

This wet crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 5.88, 4.70, 4.35,3.66 and 3.48 Angstroms in powder X-ray diffraction. A chart of thepowder X-ray diffraction is shown in FIG. 5.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), the enantiomer excess of the crystal was100% ee.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (B)), 0.72% of a sulfone form was present asan analogous substance in the crystal, and a sulfide form and otheranalogous substances were not present.

-   (3) A suspension of the wet crystal obtained in the    above-mentioned (2) in acetone (220 ml) was added dropwise to a    mixture of acetone (75 ml) and water (370 ml), and water (520 ml)    was added. The precipitated crystal was separated and washed with    acetone-water (acetone:water=1:3) (44 ml) and water (130 ml) to give    an (S)-form having the following interplanar spacing (d) in powder    X-ray diffraction as a wet crystal.

As a result of the powder X-ray diffraction analysis of this wetcrystal, this crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. A chart of the powder X-raydiffraction is shown in FIG. 6.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), the enantiomer excess of the crystal was100% ee.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (B)), a sulfone form, a sulfide form and otheranalogous substance were not present as analogous substances in thecrystal.

Example 5 Production Method of (S)-Form

A wet crystal (containing 35.37 g of the title compound, analogoussubstance content: 0%, enantiomer excess: 100% ee, powder X-raydiffraction chart: see FIG. 7) obtained according to Example 4 wasdissolved in ethyl acetate (340 ml). The separated aqueous layer wasseparated by partitioning and the obtained organic layer wasconcentrated under reduced pressure until the liquid amount became about100 ml. Ethyl acetate (400 ml) and active carbon (3 g) were added to theresidue, and after stirring, active carbon was removed by filtration.The filtrate was concentrated under reduced pressure until the liquidamount became about 100 ml. Heptane (1000 ml) was added dropwise to theresidue at about 40° C. The mixture was stirred at the same temperaturefor about 30 min and the crystal was separated and washed with ethylacetate-heptane (1:8, 63 ml) at about 40° C. Drying gave 35.08 g of thetitle compound (yield: 99.2%).

The results of the powder X-ray diffraction analysis of this crystal areshown in the following.

The crystal showed a powder X-ray diffraction analysis pattern havingcharacteristic peaks at interplanar spacings (d) of 11.68, 6.77, 5.84,5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41 and 3.11 Angstroms in powderX-ray diffraction. A chart of the powder X-ray diffraction is shown inFIG. 8.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), a sulfone form, a sulfide form and otheranalogous substance were not present as analogous substances in thecrystal. The enantiomer excess of the (R)-form in the crystal was 100%ee.

Reference Example 2 Production Method of Solution Containing(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleby Asymmetric Oxidization

2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-methyl]thio]benzimidazole(30.0 g, 0.085 mol, containing 31 mg of water), toluene (150 mL), water(59 mg, 0.0033 mol, total amount of water 0.0050 mol) and diethyl(+)-tartrate (3.19 mL, 0.019 mol) were mixed and heated to 50 to 55° C.Titanium(IV) isopropoxide (2.49 mL, 0.0085 mol) was added to the mixtureunder a nitrogen atmosphere, and the mixture was stirred at 50 to 55° C.for 30 min. Under a nitrogen atmosphere and under cooling,diisopropylethylamine (4.88 mL, 0.028 mol) was added to the obtainedmixture and cumene hydroperoxide (46.0 mL, 0.26 mol) was added at −5 to5° C. The mixture was stirred at −5 to 5° C. for 5.5 hr to allowreaction.

As a result of the analysis of the reaction mixture by high performanceliquid chromatography (condition (B)), 2.3% of a sulfide form and 2.0%of a sulfone form were present as analogous substances in the reactionmixture, and other analogous substances were not present.

Reference Example 3 Purification Method of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole

To the reaction mixture obtained in the above-mentioned ReferenceExample 2 was added 25% aqueous sodium thiosulfate solution (81 g) undera nitrogen stream to decompose the residual cumene hydroperoxide, andthe mixture was concentrated under reduced pressure until the liquidamount became about 150 mL. While maintaining at 0 to 10° C.,heptane-t-butyl methyl ether (heptane:t-butyl methyl ether=1:1) (120 mL)was added dropwise and then heptane (420 mL) was added dropwise. Theprecipitated crystal was separated and washed with cold heptane-t-butylmethyl ether (heptane:t-butyl methyl ether=1:1) (60 mL) to give 67.2 gof a wet crystal.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), the enantiomer excess of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolein the crystal was 98.2% ee.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (B)), 0.85% of a sulfide form and 1.7% of asulfone form were present as analogous substances in the crystal, andother analogous substances were not present.

Example 6

The wet crystal (3.00 g) obtained in the above-mentioned ReferenceExample 3 was suspended in acetone (10 mL) and water (40 mL) was addeddropwise. After stirring for 6 hr, the precipitated crystal wasseparated.

As a result of the powder X-ray diffraction analysis of this wetcrystal, this wet crystal showed a powder X-ray diffraction analysispattern having characteristic peaks at interplanar spacings (d) of 8.33,6.63, 5.86 and 4.82 Angstroms in powder X-ray diffraction. A chart ofthe powder X-ray diffraction is shown in FIG. 9.

As a result of the analysis of this wet crystal by high performanceliquid chromatography (condition (B)), 0.61% of a sulfide form and 0.56%of a sulfone form were present as analogous substances in the crystal,and other analogous substances were not present.

Example 7

The wet crystal obtained in the above-mentioned Example 6 was dried.

As a result of the powder X-ray diffraction analysis of this crystal,this crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. A chart of the powder X-raydiffraction is shown in FIG. 10.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), an enantiomer excess of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolein the crystal was 99.8% ee.

Example 8

The wet crystal (3.00 g) obtained in the above-mentioned ReferenceExample 3 was suspended in tetrahydrofuran (10 mL) and water (80 mL) wasadded dropwise. After stirring for 5 hr, the precipitated crystal wasseparated.

As a result of the powder X-ray diffraction analysis of this wetcrystal, this wet crystal showed a powder X-ray diffraction patternhaving characteristic peaks at interplanar spacings (d) of 8.33, 6.63,5.86 and 4.82 Angstroms in powder X-ray diffraction. A chart of thepowder X-ray diffraction is shown in FIG. 11.

As a result of the analysis of this wet crystal by high performanceliquid chromatography (condition (B)), 0.63% of a sulfide form and 0.50%of a sulfone form were present as analogous substances in the crystal,and other analogous substances were not present.

Example 9

The wet crystal obtained in the above-mentioned Example 8 was dried.

As a result of the powder X-ray diffraction analysis of this crystal,this crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. A chart of the powder X-raydiffraction is shown in FIG. 12.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), the enantiomer excess of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolein the crystal was 99.8% ee.

Example 10

The wet crystal (3.00 g) obtained in the above-mentioned ReferenceExample 3 was suspended in isopropanol (10 mL) and water (40 mL) wasadded dropwise. After stirring for 5 hr, the precipitated crystal wasseparated.

As a result of the powder X-ray diffraction analysis of this wetcrystal, this wet crystal showed a powder X-ray diffraction patternhaving characteristic peaks at interplanar spacings (d) of 8.33, 6.63,5.86 and 4.82 Angstroms in powder X-ray diffraction. A chart of thepowder X-ray diffraction is shown in FIG. 13.

As a result of the analysis of this wet crystal by high performanceliquid chromatography (condition (B)), 0.68% of a sulfide form and 0.64%of a sulfone form were present as analogous substances in the crystal,and other analogous substances were not present.

Example 11

The wet crystal obtained in the above-mentioned Example 10 was dried.

As a result of the powder X-ray diffraction analysis of this crystal,this crystal showed a powder X-ray diffraction analysis pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. A chart of the powder X-raydiffraction is shown in FIG. 14.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), the enantiomer excess of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolein the crystal was 99.7% ee.

Example 12

The wet crystal (3.00 g) obtained in the above-mentioned ReferenceExample 3 was suspended in N,N-dimethylformamide (10 mL) and water (40mL) was added dropwise. After stirring for 5 hr, the precipitatedcrystal was separated.

As a result of the powder X-ray diffraction analysis of this wetcrystal, this wet crystal showed a powder X-ray diffraction patternhaving characteristic peaks at interplanar spacings (d) of 8.33, 6.63,5.86 and 4.82 Angstroms in powder X-ray diffraction. A chart of thepowder X-ray diffraction is shown in FIG. 15.

As a result of the analysis of this wet crystal by high performanceliquid chromatography (condition (B)), 0.70% of a sulfide form and 0.41%of a sulfone form were present as analogous substances in the crystal,and other analogous substances were not present.

Example 13

The wet crystal obtained in the above-mentioned Example 12 was dried.

As a result of the powder X-ray diffraction analysis of this crystal,this crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. A chart of the powder X-raydiffraction is shown in FIG. 16.

As a result of the analysis of this crystal by high performance liquidchromatography (condition (A)), the enantiomer excess of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolein the crystal was 99.7% ee.

Example 14

The wet crystal (3.00 g) obtained in the above-mentioned ReferenceExample 3 was suspended in methanol (10 mL) and water (40 mL) was addeddropwise. After stirring for 6 hr, the precipitated crystal wasseparated.

As a result of the powder X-ray diffraction analysis of this wetcrystal, this wet crystal showed a powder X-ray diffraction patternhaving characteristic peaks at interplanar spacings (d) of 8.33, 6.63,5.86 and 4.82 Angstroms in powder X-ray diffraction. A chart of thepowder X-ray diffraction is shown in FIG. 17.

As a result of the analysis of this wet crystal by high performanceliquid chromatography (condition (A)), the enantiomer excess of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolein the crystal was 99.5% ee.

As a result of the analysis of this wet crystal by high performanceliquid chromatography (condition (B)), 0.72% of a sulfide form and 0.60%of a sulfone form were present as analogous substances in the crystal,and other analogous substances were not present.

Example 15

The wet crystal obtained in the above-mentioned Example 14 was dried.

As a result of the powder X-ray diffraction analysis of this crystal,this crystal showed a powder X-ray diffraction analysis pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. A chart of the powder X-raydiffraction is shown in FIG. 18.

Example 16

The wet crystal (3.00 g) obtained in the above-mentioned ReferenceExample 3 was suspended in ethanol (10 mL) and water (40 mL) was addeddropwise. After stirring for 6 hr, the precipitated crystal wasseparated.

As a result of the powder X-ray diffraction analysis of this wetcrystals, this wet crystal showed a powder X-ray diffraction patternhaving characteristic peaks at interplanar spacings (d) of 8.33, 6.63,5.86 and 4.82 Angstroms in powder X-ray diffraction. A chart of thepowder X-ray diffraction is shown in FIG. 19.

As a result of the analysis of this wet crystal by high performanceliquid chromatography (condition (A)), the enantiomer excess of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolein the crystal was 100% ee.

As a result of the analysis of this wet crystal by high performanceliquid chromatography (condition (B)), 0.68% of a sulfide form and 0.63%of a sulfone form were present as analogous substances in the crystal,and other analogous substances were not present.

Example 17

The wet crystal obtained in the above-mentioned Example 16 was dried.

As a result of the powder X-ray diffraction analysis of this crystal,this crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. A chart of the powder X-raydiffraction is shown in FIG. 20.

Example 18

The wet crystal (3.00 g) obtained in the above-mentioned ReferenceExample 3 was suspended in acetonitrile (10 mL) and water (40 mL) wasadded dropwise. After stirring for 6 hr, the precipitated crystal wasseparated.

As a result of the powder X-ray diffraction analysis of this wetcrystal, this wet crystal showed a powder X-ray diffraction patternhaving characteristic peaks at interplanar spacings (d) of 8.33, 6.63,5.86 and 4.82 Angstroms in powder X-ray diffraction. A chart of thepowder X-ray diffraction is shown in FIG. 21.

As a result of the analysis of this wet crystal by high performanceliquid chromatography (condition (A)), the enantiomer excess of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolein the crystal was 100% ee.

As a result of the analysis of the wet crystal by high performanceliquid chromatography (condition (B)), 0.80% of a sulfide form and 0.33%of a sulfone form were present as analogous substances in the crystal,and other analogous substances were not present.

Example 19

The wet crystal obtained in the above-mentioned Example 18 was dried.

As a result of the powder X-ray diffraction analysis of this crystal,this crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. A chart of the powder X-raydiffraction is shown in FIG. 22.

Example 20

The wet crystal (3.00 g) obtained in the above-mentioned ReferenceExample 3 was suspended in dimethyl sulfoxide (10 mL) and water (40 mL)was added dropwise. After stirring for 7 hr, the precipitated crystalwas separated.

As a result of the powder X-ray diffraction analysis of this wetcrystal, this wet crystal showed a powder X-ray diffraction patternhaving characteristic peaks at interplanar spacings (d) of 8.33, 6.63,5.86 and 4.82 Angstroms in powder X-ray diffraction. A chart of thepowder X-ray diffraction is shown in FIG. 23.

As a result of the analysis of this wet crystal by high performanceliquid chromatography (condition (A)), the enantiomer excess of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolein the crystal was 99.6% ee.

As a result of the analysis of the wet crystal by high performanceliquid chromatography (condition (B)), 0.79% of a sulfide form and 0.37%of a sulfone form were present as analogous substances in the crystal,and other analogous substances were not present.

Example 21

The wet crystal obtained in the above-mentioned Example 20 was dried.

As a result of the powder X-ray diffraction analysis of this crystal,this crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at interplanar spacings (d) of 8.33, 6.63, 5.86 and4.82 Angstroms in powder X-ray diffraction. A chart of the powder X-raydiffraction is shown in FIG. 24.

Industrial Applicability

According to the production method of the present invention, a sulfoneform difficult to remove, which is contained in an (R)-form or a saltthereof or an (S)-form or a salt thereof, can be removed easily, and acrystal of an (R)-form or a salt thereof or an (S)-form or a saltthereof having an extremely high enantiomer excess can be producedefficiently at an industrial large scale in high yield by a convenientmethod.

1. A production method for a crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.n′H₂O(wherein n′ is about 0 to about 0.1) or a salt thereof bycrystallization from an organic solvent solution or suspension in which(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.nH₂O(wherein n is about 0.1 to about 1.0) or a salt thereof has beendissolved or suspended.
 2. The production method according to claim 1,wherein(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.nH₂O(wherein n is about 0.1 to about 1.0) or a salt thereof is subjected toa dehydration step, followed by crystallization for the objectivecrystal.
 3. The production method according to claim 1, wherein theorganic solvent comprises an acetic acid C₁₋₄ alkyl ester.
 4. Theproduction method according to claim 3, wherein the acetic acid C₁₋₄alkyl ester is ethyl acetate.
 5. The production method according toclaim 1, wherein n is about 0.2 to about 0.8.
 6. The production methodaccording to claim 1 wherein n is about 0.5.
 7. A production method fora crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.n′H₂O(wherein n′ is about 0 to about 0.1) or a salt thereof, which issubstantially free of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof, which method comprises obtaining a crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.nH₂O(wherein n is about 0.1 to about 1.0) or a salt thereof by way of aselective crystallization from a solution or suspension comprising(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof in a greater amount than(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof, followed by crystallization for the objective crystalfrom an organic solvent solution or suspension in which the obtainedcrystal has been dissolved or suspended.
 8. The production methodaccording to claim 7, wherein the selective crystallization is conductedin an organic solvent containing water.
 9. The production methodaccording to claim 8, wherein the organic solvent is one kind or morekinds selected from esters, ketones, ethers, hydrocarbons and aromatichydrocarbons.
 10. A production method for a crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof, which is substantially free of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof, which method comprises obtaining a crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof by a selective crystallization from a solutioncomprising(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof in a greater amount than(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof and subjecting the obtained crystal to a dehydrationstep, followed by crystallization for the objective crystal.
 11. Aproduction method for a crystal of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.m′H₂O(wherein m′ is about 0 to about 0.1) or a salt thereof, which comprisesobtaining the objective crystal by crystallization from an organicsolvent solution or suspension in which(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.mH₂O(wherein m is about 0.1 to about 1.0) or a salt thereof has beendissolved or suspended.
 12. The production method according to claim 11,wherein(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.mH₂O(wherein m is about 0.1 to about 1.0) or a salt thereof is subjected toa dehydration step, followed by crystallization for the objectivecrystal.
 13. The production method according to claim 11, wherein theorganic solvent comprises an acetic acid C₁₋₄ alkyl ester.
 14. Theproduction method according to claim 13, wherein the acetic acid C₁₋₄alkyl ester is ethyl acetate.
 15. The production method according toclaim 11, wherein n is about 0.2 to about 0.8.
 16. The production methodaccording to claim 11 wherein n is about 0.5.
 17. A production methodfor a crystal of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.m′H₂O(wherein m′ is about 0 to about 0.1) or a salt thereof, which issubstantially free of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof, which method comprises obtaining a crystal of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.mH₂O(wherein m is about 0.1 to about 1.0) or a salt thereof by a selectivecrystallization from a solution or suspension comprising(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof in a greater amount than(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof, followed by crystallization for the objective crystalfrom an organic solvent solution or suspension in which the obtainedcrystal has been dissolved or suspended.
 18. The production methodaccording to claim 17, wherein the selective crystallization isconducted in an organic solvent containing water.
 19. The productionmethod according to claim 18, wherein the organic solvent is one kind ormore kinds selected from esters, ketones, ethers, hydrocarbons andaromatic hydrocarbons.
 20. A production method for a crystal of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof, which is substantially free of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof, which method comprises obtaining a crystal of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof by a selective crystallization from a solutioncomprising(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof in a greater amount than(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof, and subjecting the obtained crystal to a dehydrationstep, followed by crystallization for the objective crystal.
 21. Theproduction method according to claim 7, wherein(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof or(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof in the solution or suspension shows an enantiomerexcess of not less than about 80% ee.
 22. The production methodaccording to claim 7, wherein the crystal obtained by the selectivecrystallization is farther subjected to one or more times of acrystallization step.
 23. The production method according to claim 10,wherein(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof or(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof in the solution or suspension shows an enantiomerexcess of not less than about 80% ee.
 24. The production methodaccording to claim 17, wherein(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof or—(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof in the solution or suspension shows an enantiomerexcess of not less than about 80% ee.
 25. The production methodaccording to claim 20, wherein(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof or(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof in the solution or suspension shows an enantiomerexcess of not less than about 80% ee.
 26. The production methodaccording to claim 10, wherein the crystal obtained by the selectivecrystallization is further subjected to one or more times of acrystallization step.
 27. The production method according to claim 17,wherein the crystal obtained by the selective crystallization is farthersubjected to one or more times of a crystallization step.
 28. Theproduction method according to claim 20, wherein the crystal obtained bythe selective crystallization is further subjected to one or more timesof a crystallization step.
 29. A method for producing a crystal of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.m′H₂O,wherein m′ is about 0 to about 0.1, or a salt thereof, which issubstantially free of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof, comprising: (i) obtaining a crystal of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.mH₂O,wherein m is about 0.1 to about 1.0, or a salt thereof by a selectivecrystallization from a solution or suspension comprising(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]-sulfinyl]benzimidazoleor a salt thereof in a greater amount than(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof, wherein the selective crystallization is conducted inan organic solvent containing water; (ii) subjecting the obtainedcrystal to a dehydration step followed by (iii) crystallization for theobjective crystal from an organic solvent solution or suspension inwhich said obtained crystal has been dissolved or suspended.
 30. Amethod for producing a crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.n′H₂O,wherein n′ is about 0 to about 0.1, or a salt thereof, which issubstantially free of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof comprising: (i) obtaining a crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole.nH₂O,wherein n is about 0.1 to about 1.0, or a salt thereof by a selectivecrystallization from a solution or suspension comprising(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof in a greater amount than(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazoleor a salt thereof wherein the selective crystallization is conducted inan organic solvent containing water; (ii) subjecting the obtainedcrystal to a dehydration step, followed by (iii) crystallization for theobjective crystal from an organic solvent solution or suspension inwhich said obtained crystal has been dissolved or suspended.